Deep Brain Stimulation of the Medial Septal Area Can Modulate Gene Expression in the Hippocampus of Rats under Urethane Anesthesia

Abstract

We studied the effects of stimulation of the medial septal area on the gene expression in the dorsal and ventral hippocampus. Rats under urethane anesthesia were implanted with a recording electrode in the right hippocampus and stimulating electrode in the dorsal medial septum (dMS) or medial septal nucleus (MSN). After one-hour-long deep brain stimulation, we collected ipsi- and contralateral dorsal and ventral hippocampi. Quantitative PCR showed that deep brain stimulation did not cause any changes in the intact contralateral dorsal and ventral hippocampi. A comparison of ipsi- and contralateral hippocampi in the control unstimulated animals showed that electrode implantation in the ipsilateral dorsal hippocampus led to a dramatic increase in the expression of immediate early genes (c-fos, arc, egr1, npas4), neurotrophins (ngf, bdnf) and inflammatory cytokines (il1b and tnf, but not il6) not only in the area close to implantation site but also in the ventral hippocampus. Moreover, the stimulation of MSN but not dMS further increased the expression of c-fos, egr1, npas4, bdnf, and tnf in the ipsilateral ventral but not dorsal hippocampus. Our data suggest that the activation of medial septal nucleus can change the gene expression in ventral hippocampal cells after their priming by other stimuli.

Keywords: bdnf; deep brain stimulation; dorsal hippocampus; early genes; inflammation; ngf; septum; ventral hippocampus.

Figure 1

Field responses recorded in the hippocampal CA1 area following stimulation of medial septal area at different depths. Panel (A) shows localization of stimulating electrodes. Examples of fEPSP after stimulation of dMS (B) and MSN (C,D) are shown.

Figure 2

Effect of stimulation of the medial septum on the hippocampal EEG. (A), LFP time series of: control rats (red line), dMS rats (blue), MSN rats (green); (B), corresponding power spectra; (C), corresponding averaged power in frequency range [0.5–4] Hz.

Figure 3

Changes in the expression of early genes after stimulation of the dorsal medium septum (dMS) and medial septal nucleus (MSN) in dorsal and ventral parts (DH and VH, respectively) of the left (intact) and right (damaged by implanted electrode) hippocampi. p-values are shown for Kruskal–Wallis test for comparison of three groups in one hemisphere. Interhemispheric comparisons were performed only in the control group using the Mann–Whitney test. For the intergroup comparisons, *, **, and *** mark significant differences at 0.005 ≤ p < 0.025, p < 0.005, and p < 0.0005 (post hoc Dunn test). For interhemispheric comparisons, *, **, and *** mark significant differences at p ≤ 0.05, p < 0.01, and p < 0.001 (Mann–Whitney test).

Figure 4

Changes in the expression of neurotrophins after stimulation of the dorsal medium septum and medial septal nucleus in dorsal and ventral parts (DH and VH, respectively) of the left (intact) and right (damaged by implanted electrode) hippocampi. p-values are shown for Kruskal–Wallis test for comparison of three groups in one hemisphere. Interhemispheric comparisons were performed only in the control group using the Mann–Whitney test. For the intergroup comparisons, *, **, and *** mark significant differences at 0.005 ≤ p < 0.025, p < 0.005, and p < 0.0005 (post hoc Dunn test). For interhemispheric comparisons, *, **, and *** mark significant differences at p ≤ 0.05, p < 0.01, and p < 0.001 (Mann–Whitney test).

Figure 5

Changes in the expression of inflammatory cytokines after stimulation of the dorsal medium septum and medial septal nucleus in dorsal and ventral parts (DH and VH, respectively) of the left (intact) and right (damaged by implanted electrode) hippocampi. p-values are shown for Kruskal–Wallis test for comparison of three groups in one hemisphere. Interhemispheric comparisons were performed only in the control group using the Mann–Whitney test. For interhemispheric comparisons, ** mark significant differences at p < 0.01 (Mann–Whitney test).